Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells

Abstract

During viral entry, enveloped viruses require the fusion of their lipid envelope with host cell membranes. For coronaviruses, this critical step is governed by the virally-encoded spike (S) protein, a class I viral fusion protein that has several unique features. Coronavirus entry is unusual in that it is often biphasic in nature, and can occur at or near the cell surface or in late endosomes. Recent advances in structural, biochemical and molecular biology of the coronavirus S protein has shed light on the intricacies of coronavirus entry, in particular the molecular triggers of coronavirus S-mediated membrane fusion. Furthermore, characterization of the coronavirus fusion peptide (FP), the segment of the fusion protein that inserts to a target lipid bilayer during membrane fusion, has revealed its particular attributes which imparts some of the unusual properties of the S protein, such as Ca-dependency. These unusual characteristics can explain at least in part the biphasic nature of coronavirus entry. In this review, using severe acute respiratory syndrome coronavirus (SARS-CoV) as model virus, we give an overview of advances in research on the coronavirus fusion peptide with an emphasis on its role and properties within the biological context of host cell entry.

An exploration of conditions proposed to trigger the Ebola virus glycoprotein for fusion

“…Because of these conflicting conclusions we re-examined the sufficiency of NPC1 to trigger the fusion activity of EBOV GP cl. In the process, we also assessed the potential enhancing role of additional factors shown, as outlined in the Results section, to augment fusion of other endocytosed enveloped viruses [23,[33][34][35]38,39,45,50,53]. Our findings are consistent with and extend the result stated by Miller et al [10].…”

“…For most other enveloped viruses that enter cells through endosomes, even for Lassa virus, the second virus shown to use an intracellular/endosomal receptor [12,13], low pH is then sufficient to trigger conformational changes that elicit the fusion activity of the viral fusion GP [16]. The fusion GPs of SARS and MERS coronaviruses additionally require a (post receptor binding) endosomal proteolytic cleavage event [50][51][52][53].…”

“…Based on findings stated by Miller et al [10] and presented in Figs 1, 2 and 5, we postulated that a factor(s) in addition to low pH and NPC1 is needed to elicit the fusion activity of EBOV GP cl . We therefore tested factors required for fusion or uncoating of other endocytosed enveloped viruses (Ca ++ , K + , BMP, proteases) [38,39,41,45,53], proposed for EBOV in particular (Ca ++ , additional cathepsin action, reducing agent) [6,25,55], and even the non-physiological condition of elevated temperature, which can substitute for biological viral fusion triggers [33][34][35]. However, none of these factors or treatments elicited detectable CCF between effector cells bearing EBOV GP cl and target cells bearing NPC1 or its C-Loop (at any pH tested), while robust CCF was consistently detected with effector cells bearing LCMV GP at low pH.…”

HOPS-dependent endosomal fusion required for efficient cytosolic delivery of therapeutic peptides and small proteins

“…The HOPS complex has also been implicated in the cytosolic trafficking of numerous bacterial, fungal, and viral pathogens, including coronavirus (CoV) (89,90), the Ebola virus (91), Fusarium graminearum (92), Candida albicans (93), Cryptococcus neoformans (94), and Aspergillus nidulans (95). In particular, although their genomes lack sequences encoding a canonical penta-Arg motif, both CoV and Ebola require HOPS during the later steps of their postulated mechanism of cell entry: after the viral particle has been endocytosed but before it reaches the cytosol.…”

The SARS-CoV-2 outbreak from a one health perspective

“…Coronaviruses are enveloped viruses like influenza, HIV, rabies etc, their envelope composed of a lipid bilayer, which the virus acquires from the host cell membrane while releasing from the infected cells [38]. Using lipid solvents and detergents was proved to inactivate SARS-CoV through permeant damage of the lipid components of the viral envelope [39].…”